Currently there are many drugs available for the treatment of disorders of the central nervous system. Among these drugs is a category known as antipsychotics for treating serious mental conditions such as schizophrenia and schizophreniform illnesses. The drugs available for such conditions are often associated with undesirable adverse events, and there is a need for better products that control or eliminate the symptoms in a safer and more effective way.
Patients suffering from schizophrenia, a condition of unknown etiology, exhibit a group of both positive and negative symptoms. Positive symptoms include delusions, hallucinations, disordered thoughts, and disorganized speech, while negative symptoms include flat affect, anhedonia, social withdrawal, emotional detachment, cognitive deficits, and poverty of speech. Not only does schizophrenia cause personal suffering by the patient, it also severely affects the patient's occupational and social functions, so that often the patient must be institutionalized, which results in a high cost to society.
A leading hypothesis suggests that the positive symptoms of schizophrenia can be effectively treated by compounds that act as antagonists at certain dopamine receptors. Currently, five principal dopamine receptors (D1–D5) that have been identified. Antipsychotic efficacy has been most closely associated with blockade of the D2 class of dopamine receptors. The typical antipsychotic agents (eg. haloperidol) are effective in controlling the positive symptoms of schizophrenia but do not adequately treat the negative symptoms and also induce significant adverse events, principally extrapyramidal side effects, hyperprolactinemia, and tardive dyskinesia.
One approach to developing better antipsychotic agents, involves the identification of compounds that combine D2 receptor blockade with actions at other receptors. One such agent is clozapine.
Clozapine was the first drug identified as an “atypical” antipsychotic, i.e., a drug effective in treating both the positive and negative symptoms of schizophrenia. Additionally, it did not cause EPS and the other adverse events seen with classical, “typical” antipsychotics. Although clozapine is an effective drug, its utility in treating schizophrenia has been limited because of the clinical observation that 1–2% of treated patients developed a potentially fatal blood disorder. More recently, olanzapine has been widely accepted as an atypical antipsychotic with relatively few adverse events. Atypical antipsychotics like clozapine and olanzapine are D2 receptor antagonists and also interact with receptor subtypes for several neurotransmitters, including dopamine, serotonin, norepinephrine, histamine, and acetylcholine. It is believed that some of these additional receptor activities are responsible for the improved efficacy of the atypical antipsychotics and that the adverse events of these agents may be mediated by interactions with others. The success of the atypical antipsychotic drugs has inspired research to produce even more effective drugs for the treatment of schizophrenia that would have negligible instances of adverse events.
The present invention provides antipsychotic compounds and methods of using those compounds to treat psychotic disorders, in particular, schizophrenia and mood disorders, such as bipolar disorders. These compounds offer certain improvements and advantages over the antipsychotics currently in clinical use.